Age effects on neurochemical markers and the correlation between brain neurochemical markers and motor performance were tested in C57BL/6J and A/J mice. Motor performance was altered by age, and age effects varied with genetic strain. Age-associated decrements in performance were correlated with regional brain changes in cholinergic, GABAergic, and catecholaminergic neurochemical markers. Activities of choline acetyltransferase (CAT), glutamic acid decarboxylase (GAD), and tyrosine hydroxylase (TH) were assayed in four brain regions after animals were evaluated in a battery of psychomotor tests. Significant correlations between enzyme activity and motor performance occurred most frequently in the youngest (4-mo.) and oldest (24-mo.) groups. Examination of age effects on the cholinergic markers, CAT activity and muscarinic binding in C57BL/6J mice revealed regional increases in CAT activity that were associated with increases in Vmax, and no changes in Km. These increases in Vmax for CAT were associated with decreases in the densities of muscarinic binding sites in the cortex and striatum and increases in the densities of muscarinic binding sites in the hippocampus. There were no age changes in the affinities of muscarinic ligands or the percent of high affinity muscarinic binding sites in any region. A study of CAT and muscarinic binding in regions of brains of normal men and of patients who died of Alzheimer's disease revealed decreases in CAT activity that were associated with increases in total muscarinic binding. There were no differences in the percentage of total muscarinic receptor binding associated with the high affinity binding sites between control and Alzheimer's diseased tissues. These findings suggest that a presynaptic cholinergic defect in Alzheimer's disease is associated with muscarinic receptor upregulation.